Human viral hemorrhagic fevers are caused by four virus families all of which are enveloped RNA viruses (Geisbert T W, Jahrling P B. Exotic emerging viral diseases: progress and challenges. Nat Med 2004; 10:S110-21). Hemorrhagic fever caused by the filoviruses, Marburg virus (MARV) and Ebola virus (EBOV), exhibit the highest mortality rates ranging from 23-90% in humans (Feldmann et al., Filoviridae: Marburg and Ebola Viruses. In: Knipe D M, Howley P M, eds. Fields Virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2013:923-56). Filoviruses remain endemic to Central Africa and sporadic lethal outbreaks continue to occur. Despite the severity of disease caused by filoviruses, no licensed vaccine or therapeutic is currently available.
MARV possess a single-stranded RNA genome of approximately 19 kb encoding seven genes: NP (nucleoprotein), VP35 (polymerase cofactor), VP40 (matrix protein), GP (glycoprotein), VP30 (transcription activator), VP24 (secondary matrix protein), and a RNA-dependent RNA polymerase (L polymerase). Current therapeutic strategies consist of passive antibody therapy, which has demonstrated protection of nonhuman primates (NHP) against MARV-Ci67 using polyclonal NHP IgG (Dye et al. Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease. Proc Natl Acad Sci USA 2012; 109:5034-9) and morpholino oligomers (PMOs), which protected NHPs against MARV-Musoke (Warren et al., Advanced antisense therapies for postexposure protection against lethal filovirus infections. Nat Med 2010; 16:991-4). These therapeutic strategies have not been shown to confer protection against MARV-Angola which causes higher mortality rates in man and a faster disease course in NHPs (Towner et al., Marburg virus genomics and association with a large hemorrhagic fever outbreak in Angola. J Virol 2006; 80:6497-516; Geisbert et al., Marburg virus Angola infection of rhesus macaques: pathogenesis and treatment with recombinant nematode anticoagulant protein c2. J Infect Dis 2007; 196 Suppl 2:S372-81).
Thus, there is a continuing need for compositions and methods for the treatment of Marburg Virus infection in humans, in particular treatment of infection with MARV-Angola.